Devices and methods for nerve stimulation

ABSTRACT

Methods and devices for stimulating a nerve in a patient include emitting an electrical signal near a spinal nerve within the patient such that the patient experiences at least some pain relief. The methods include varying an electric field such that burst periods and constant periods are created. The electric field has a charge that alternates between positive and negative during the burst periods and a charge with a magnitude of zero during the constant periods.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. Non-Provisional applicationSer. No. 16/837,818, filed Apr. 1, 2020, which is a Divisional of U.S.Non-Provisional application Ser. No. 16/520,630, filed Jul. 24, 2019,which is a Divisional of U.S. Non-Provisional application Ser. No.15/149,406 filed 9 May 2016 (now U.S. Pat. No. 10,363,415 issued Jul.30, 2019); which is a Divisional of U.S. Non-Provisional applicationSer. No. 14/337,930 filed 22 Jul. 2014 now U.S. Pat. No. 9,333,347issued 10 May 2016; which is a Continuation of U.S. Non-Provisionalapplication Ser. No. 13/075,746 filed 30 Mar. 2011 now U.S. Pat. No.8,874,205 issued 28 Oct. 2015, which (i) claims the benefit of priorityto U.S. Provisional Application Ser. No. 61/451,259 filed 10 Mar. 2011,and (ii) is a Continuation in Part of U.S. Non-Provisional applicationSer. No. 12/964,050 filed 9 Dec. 2010, which (i) claims the benefit ofpriority to U.S. Provisional Application Ser. No. 61/415,469 filed 19Nov. 2010, and (ii) is a Continuation in Part of U.S. Non-Provisionalapplication Ser. No. 12/859,568 filed 19 Aug. 2010 now U.S. Pat. No.9,037,247 issued 19 May 2015; each of which is fully incorporated byreference herein for all purposes.

BACKGROUND

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Itrelates more specifically to the use of non-invasive devices andmethods, particularly transcutaneous electrical nerve stimulationdevices, as well as methods of treating patients using energy that isdelivered by such devices. The disclosed methods and devices may be usedto stimulate the vagus nerve of a patient to treat many conditions, suchas: headaches such as migraine headaches, tension headaches, sinusheadaches, cluster headaches and the like, allergic rhinitis,post-operative ileus, dysfunction associated with TNF-alpha inAlzheimer's disease, postoperative cognitive dysfunction, postoperativedelirium, rheumatoid arthritis, asthmatic bronchoconstriction, urinaryincontinence and/or overactive bladder, and sphincter of Oddidysfunction, as well as neurodegenerative diseases more generally,including essential tremor, Alzheimer's disease and its precursor mildcognitive impairment (MCI), Parkinson's disease (including Parkinson'sdisease dementia) and multiple sclerosis.

Treatments for various infirmities sometime require the destruction ofotherwise healthy tissue in order to produce a beneficial effect.Malfunctioning tissue is identified and then lesioned or otherwisecompromised in order to produce a beneficial outcome, rather thanattempting to repair the tissue to its normal functionality. A varietyof techniques and mechanisms have been designed to produce focusedlesions directly in target nerve tissue, but collateral damage isinevitable.

Other treatments for malfunctioning tissue can be medicinal in nature,but in many cases the patients become dependent upon artificiallysynthesized chemicals. In many cases, these medicinal approaches haveside effects that are either unknown or quite significant.Unfortunately, the beneficial outcomes of surgery and medicines areoften realized at the cost of function of other tissues, or risks ofside effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue holds significant promise for the treatment ofmany ailments, because such stimulation is generally a wholly reversibleand non-destructive treatment.

Nerve stimulation is thought to be accomplished directly or indirectlyby depolarizing a nerve membrane, causing the discharge of an actionpotential; or by hyperpolarization of a nerve membrane, preventing thedischarge of an action potential. Such stimulation may occur afterelectrical energy, or also other forms of energy, are transmitted to thevicinity of a nerve [F. RATTAY. The basic mechanism for the electricalstimulation of the nervous system. Neuroscience 89 (2, 1999):335-346;Thomas HEIMBURG and Andrew D. Jackson. On solution propagation inbiomembranes and nerves. PNAS 102 (28, 2005): 9790-9795]. Nervestimulation may be measured directly as an increase, decrease, ormodulation of the activity of nerve fibers, or it may be inferred fromthe physiological effects that follow the transmission of energy to thenerve fibers.

One of the most successful applications of modern understanding of theelectrophysiological relationship between muscle and nerves is thecardiac pacemaker. Although origins of the cardiac pacemaker extend backinto the 1800's, it was not until 1950 that the first practical, albeitexternal and bulky, pacemaker was developed. The first truly functional,wearable pacemaker appeared in 1957, and in 1960, the first fullyimplantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by stimulating thesacral nerve roots at the bottom of the spinal cord (see U.S. Pat. No.6,871,099 to WHITEHURST, et al., the disclosure of which is incorporatedherein by reference).

Electrical stimulation of the brain with implanted electrodes has alsobeen approved for use in the treatment of various conditions, includingmovement disorders such as essential tremor and Parkinson's disease. Theprinciple underlying these approaches involves disruption and modulationof hyperactive neuronal circuit transmission at specific sites in thebrain. Unlike potentially dangerous lesioning procedures in whichaberrant portions of the brain are physically destroyed, electricalstimulation is achieved by implanting electrodes at these sites. Theelectrodes are used first to sense aberrant electrical signals and thento send electrical pulses to locally disrupt pathological neuronaltransmission, driving it back into the normal range of activity. Theseelectrical stimulation procedures, while invasive, are generallyconducted with the patient conscious and a participant in the surgery.

However, brain stimulation, and deep brain stimulation in particular, isnot without some drawbacks. The procedure requires penetrating theskull, and inserting an electrode into brain matter using acatheter-shaped lead, or the like. While monitoring the patient'scondition (such as tremor activity, etc.), the position of the electrodeis adjusted to achieve significant therapeutic potential. Next,adjustments are made to the electrical stimulus signals, such asfrequency, intervalicity, voltage, current, etc., again to achievetherapeutic results. The electrode is then permanently implanted, andwires are directed from the electrode to the site of a surgicallyimplanted pacemaker. The pacemaker provides the electrical stimulussignals to the electrode to maintain the therapeutic effect. While thetherapeutic results of deep brain stimulation are promising, significantcomplications may arise from the implantation procedure, includingstroke induced by damage to surrounding tissues and theneuro-vasculature.

Most of the above-mentioned applications of electrical stimulationinvolve the surgical implantation of electrodes within a patient. Incontrast, for embodiments of the present invention, the discloseddevices and medical procedures stimulate nerves by transmitting energyto nerves and tissue non-invasively. They may offer the patient analternative that does not involve surgery. A medical procedure isdefined as being non-invasive when no break in the skin (or othersurface of the body, such as a wound bed) is created through use of themethod, and when there is no contact with an internal body cavity beyonda body orifice (e.g, beyond the mouth or beyond the external auditorymeatus of the ear). Such non-invasive procedures are distinguished frominvasive procedures (including minimally invasive procedures) in thatinvasive procedures do involve inserting a substance or device into orthrough the skin or into an internal body cavity beyond a body orifice.For example, transcutaneous electrical nerve stimulation (TENS) isnon-invasive because it involves attaching electrodes to the surface ofthe skin (or using a form-fitting conductive garment) without breakingthe skin. In contrast, percutaneous electrical stimulation of a nerve isminimally invasive because it involves the introduction of an electrodeunder the skin, via needle-puncture of the skin (see commonly assignedco-pending US Patent Application 2010/0241188, entitled PercutaneousElectrical Treatment of Tissue to ERRICO et al, which is herebyincorporated by reference in its entirety).

Potential advantages of non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures generally present fewer problems withbiocompatibility. In cases involving the attachment of electrodes,non-invasive methods have less of a tendency for breakage of leads, andthe electrodes can be easily repositioned if necessary. Non-invasivemethods are sometimes painless or only minimally painful and may beperformed without the need for even local anesthesia. Less training maybe required for use of non-invasive procedures by medical professionals.In view of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace, and the cost of non-invasive procedures may be reducedrelative to comparable invasive procedures.

Electrodes that are applied non-invasively to the surface of the bodyhave a long history, including electrodes that were used to stimulateunderlying nerves [L. A. GEDDES. Historical Evolution of Circuit Modelsfor the Electrode-Electrolyte Interface. Annals of BiomedicalEngineering 25 (1997):1-14]. However, electrical stimulation of nervesin general fell into disfavor in middle of the twentieth century, untilthe “gate theory of pain” was introduced by Melzack and Wall in 1965.This theory, along with advances in electronics, reawakened interest inthe use of implanted electrodes to stimulate nerves, initially tocontrol pain. Screening procedures were then developed to determinesuitable candidates for electrode implantation, which involved firstdetermining whether the patient responded when stimulated withelectrodes applied to the surface of the body in the vicinity of thepossible implant. It was subsequently found that the surface stimulationoften controlled pain so well that there was no need to implant astimulating electrode [Charles Burton and Donald D. Maurer. PainSuppression by Transcutaneous Electronic Stimulation. IEEE Transactionson Biomedical Engineering BME-21(2, 1974): 81-88]. Such non-invasivetranscutaneous electrical nerve stimulation (TENS) was then developedfor treating different types of pain, including pain in a joint or lowerback, cancer pain, post-operative pain, post-traumatic pain, and painassociated with labor and delivery [Steven E. ABRAM. TranscutaneousElectrical Nerve Stimulation. pp 1-10 in: Joel B. Myklebust, ed. Neuralstimulation (Volume 2). Boca Raton, Fla. CRC Press 1985; WALSH DM, LoweA S, McCormack K. Willer J-C, Baxter G D, Allen J M. Transcutaneouselectrical nerve stimulation: effect on peripheral nerve conduction,mechanical pain threshold, and tactile threshold in humans. Arch PhysMed Rehabil 79(1998):1051-1058; J A CAMPBELL. A critical appraisal ofthe electrical output characteristics of ten transcutaneous nervestimulators. Clin. phys. Physiol. Meas. 3(2,1982): 141-150; Patents U.S.Pat. No. 3,817,254, entitled Transcutaneous stimulator and stimulationmethod, to Maurer; U.S. Pat. No. 4,324,253, entitled Transcutaneous paincontrol and/or muscle stimulating apparatus, to Greene et al; U.S. Pat.No. 4,503,863, entitled Method and apparatus for transcutaneouselectrical stimulation, to Katims; U.S. Pat. No. 5,052,391, entitledHigh frequency high intensity transcutaneous electrical nerve stimulatorand method of treatment, to Silberstone et al; U.S. Pat. No. 6,351,674,entitled Method for inducing electroanesthesia using high frequency,high intensity transcutaneous electrical nerve stimulation, toSilverstone].

As TENS was being developed to treat pain, non-invasive electricalstimulation using surface electrodes was simultaneously developed foradditional therapeutic or diagnostic purposes, which are knowncollectively as electrotherapy. Neuromuscular electrical stimulation(NMES) stimulates normally innervated muscle in an effort to augmentstrength and endurance of normal (e.g., athletic) or damaged (e.g.,spastic) muscle. Functional electrical stimulation (FES) is used toactivate nerves innervating muscle affected by paralysis resulting fromspinal cord injury, head injury, stroke and other neurologicaldisorders, or muscle affected by foot drop and gait disorders. FES isalso used to stimulate muscle as an orthotic substitute, e.g., replace abrace or support in scoliosis management. Another application of surfaceelectrical stimulation is chest-to-back stimulation of tissue, such asemergency defibrillation and cardiac pacing. Surface electricalstimulation has also been used to repair tissue, by increasingcirculation through vasodilation, by controlling edema, by healingwounds, and by inducing bone growth. Surface electrical stimulation isalso used for iontophoresis, in which electrical currents driveelectrically charged drugs or other ions into the skin, usually to treatinflammation and pain, arthritis, wounds or scars. Stimulation withsurface electrodes is also used to evoke a response for diagnosticpurposes, for example in peripheral nerve stimulation (PNS) thatevaluates the ability of motor and sensory nerves to conduct and producereflexes. Surface electrical stimulation is also used inelectroconvulsive therapy to treat psychiatric disorders;electroanesthesia, for example, to prevent pain from dental procedures;and electrotactile speech processing to convert sound into tactilesensation for the hearing impaired. All of the above-mentionedapplications of surface electrode stimulation are intended not to damagethe patient, but if higher currents are used with special electrodes,electrosurgery may be performed as a means to cut, coagulate, desiccate,or fulgurate tissue [Mark R. Prausnitz. The effects of electric currentapplied to skin: A review for transdermal drug delivery. Advanced DrugDelivery Reviews 18 (1996) 395-425].

Despite its attractiveness, non-invasive electrical stimulation of anerve is not always possible or practical. This is primarily because thecurrent state of the art may not be able to stimulate a deep nerveselectively or without producing excessive pain, since the stimulationmay unintentionally stimulate nerves other than the nerve of interest,including nerves that cause pain. For this reason, forms of electricalstimulation other than TENS may be best suited for the treatment ofparticular types of pain [Paul F. WHITE, shitong Li and Jen W. Chiu.Electroanalgesia: Its Role in Acute and Chronic Pain Management. AnesthAnalg 92(2001):505-13].

For some other electrotherapeutic applications, it has also beendifficult to perform non-invasive stimulation of a nerve, in lieu ofstimulating that nerve invasively. The therapies most relevant to thepresent invention involve electrical stimulation of the vagus nerve inthe neck, in order to treat epilepsy, depression, and other medicalconditions. For these therapies, the left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there, then connecting the electrode to an electricalstimulator [Patent numbers U.S. Pat. No. 4,702,254 entitledNeurocybernetic prosthesis, to ZABARA; U.S. Pat. No. 6,341,236 entitledVagal nerve stimulation techniques for treatment of epileptic seizures,to OSORIO et al and U.S. Pat. No. 5,299,569 entitled Treatment ofneuropsychiatric disorders by nerve stimulation, to WERNICKE et al; G.C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brainstimulation, vagal nerve stimulation and transcranial stimulation: Anoverview of stimulation parameters and neurotransmitter release.Neuroscience and Biobehavioral Reviews 33 (2009) 1042-1060; GROVES DA,Brown VJ. Vagal nerve stimulation: a review of its applications andpotential mechanisms that mediate its clinical effects. NeurosciBiobehav Rev (2005) 29:493-500; Reese TERRY, Jr. Vagus nervestimulation: a proven therapy for treatment of epilepsy strives toimprove efficacy and expand applications. Conf Proc IEEE Eng Med BiolSoc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation:current concepts. Neurosurg Focus 25 (3,2008):E9, pp. 1-4].

When it is desired to avoid the surgical implantation of an electrode,vagal nerve stimulation (VNS) may be performed less invasively bypositioning one or more electrodes in the esophagus, trachea, or jugularvein, but with one electrode positioned on the surface of the body[Patent No. U.S. Pat. No. 7,340,299, entitled Methods of indirectlystimulating the vagus nerve to achieve controlled asystole, to PUSKAS;and U.S. Pat. No. 7,869,884, entitled Non-surgical device and methodsfor trans-esophageal vagus nerve stimulation, to SCOTT et al]. Despitetheir advantage as being non-surgical, such methods nevertheless exhibitother disadvantages associated with invasive procedures.

In other patents, non-invasive VNS is disclosed, but at a location otherthan in the neck [e.g., U.S. Pat. No. 4,865,048, entitled Method andapparatus for drug free neurostimulation, to ECKERSON; U.S. Pat. No.6,609,025 entitled Treatment of obesity by bilateral sub-diaphragmaticnerve stimulation to BARRETT et al; U.S. Pat. No. 5,458,625, entitledTranscutaneous nerve stimulation device and method for using same, toKENDALL; U.S. Pat. No. 7,386,347, entitled Electric stimulator foralpha-wave derivation, to Chung et al.; U.S. Pat. No. 7,797,042,entitled Device for applying a transcutaneous stimulus or fortranscutaneous measuring of a parameter, to Dietrich et al.; patentapplication US2010/0057154, entitled Device and Method for theTransdermal Stimulation of a Nerve of the Human Body, to Dietrich et al;US2006/0122675, entitled Stimulator for auricular branch of vagus nerve,to Libbus et al; US2008/0288016, entitled Systems and Methods forStimulating Neural Targets, to Amurthur et al]. However, because suchnon-invasive VNS occurs at a location other than the neck, it is notdirectly comparable to invasive VNS in the neck, for which therapeuticresults are well-documented. Among other patents and patentapplications, non-invasive VNS is sometimes mentioned along withinvasive VNS methods, but without addressing the problem ofunintentional stimulation of nerves other than the vagus nerve,particularly nerves that cause pain [e.g., US20080208266, entitledSystem and Method for Treating Nausea and Vomiting by Vagus NerveStimulation, to LESSER et al]. Other patents are vague as to hownon-invasive electrical stimulation in the vicinity of the vagus nervein the neck is to be accomplished [e.g., U.S. Pat. No. 7,499,747,entitled External baroreflex activation, to KIEVAL et al].

In view of the foregoing background, there is a long-felt but unsolvedneed to stimulate the vagus nerve electrically in the neck, totallynon-invasively, selectively, and essentially without producing pain. Ascompared with what would have been experienced by a patient undergoingnon-invasive stimulation with conventional TENS methods, the vagal nervestimulator should produce relatively little pain for a given depth ofstimulus penetration. Or conversely, for a given amount of pain ordiscomfort on the part of the patient (e.g., the threshold at which suchdiscomfort or pain begins), an objective of some embodiments of thepresent invention is to achieve a greater depth of penetration of thestimulus under the skin. Furthermore, an objective of some embodimentsof the present invention is to mitigate significant stimulation of othernerves and muscle that lie near the vagus nerve in the neck, butnevertheless to stimulate the vagus nerve to achieve therapeuticresults.

SUMMARY OF THE DISCLOSURE

In one aspect of the invention, devices and methods are described toproduce therapeutic effects in a patient by utilizing an energy sourcethat transmits energy non-invasively to nervous tissue. In certainembodiments, the disclosed devices can transmit energy to, or in closeproximity to, a vagus nerve in the neck of the patient, in order totemporarily stimulate, block and/or modulate electrophysiologicalsignals in that nerve. The methods that are disclosed herein comprisestimulating the vagus nerve with particular stimulation waveformparameters, preferably using the nerve stimulator devices that are alsodescribed herein.

In one aspect of the invention, a novel stimulator device is used tomodulate electrical activity of a vagus nerve or other nerves or tissue.The stimulator comprises a source of electrical power and one or moreelectrodes that are configured to stimulate a deep nerve relative to thenerve axis. The device also comprises continuous electrically conductingmedia within which the electrode(s) are in contact. The conducting mediaprovides electrically communication between the electrode(s) and thepatient's tissue such that the electrode(s) are not in direct contactwith the tissue. The conducting medium preferably has a shape thatconforms to the contour of a target body surface of a patient when themedium is applied to the target body surface

For the present medical applications, the device is ordinarily appliedto the patient's neck. In a preferred embodiment of the invention, thestimulator comprises two electrodes that lie side-by-side withinseparate stimulator heads, wherein the electrodes are separated byelectrically insulating material. Each electrode and the patient's skinare in continuous contact with an electrically conducting medium thatextends from the skin to the electrode. The conducting media fordifferent electrodes are also separated by electrically insulatingmaterial.

The source of power supplies a pulse of electric charge to theelectrode(s), such that the electrode(s) produce an electric currentand/or an electric field within the patient. The stimulator isconfigured to induce a peak pulse voltage sufficient to produce anelectric field in the vicinity of a nerve such as a vagus nerve, tocause the nerve to depolarize and reach a threshold for action potentialpropagation. By way of example, the threshold electric field forstimulation of the nerve may be about 8 V/m at about 1000 Hz. Forexample, the device may produce an electric field within the patientfrom about 10 to about 600 V/m and an electrical field gradient ofgreater than about 2 V/m/mm.

Current passing through an electrode may be from about 0 to about 40 mA,with voltage across the electrodes from about 0 to about 30 volts. Thecurrent is passed through the electrodes in bursts of pulses. There maybe from about 2 to about 20 pulses per burst, preferably from about 4 toabout 10 pulses and more preferably about five pulses. Each pulse withina burst has a duration from about 20 to about 1000 microseconds,preferably from about 100 to about 400 microseconds and more preferablyabout 200 microseconds. A burst followed by a silent inter-burstinterval repeats from about 1 to about 5000 bursts per second (bps),preferably from about 15 to about 50 bps. The preferred shape of eachpulse is a full sinusoidal wave. The preferred stimulator shapes anelongated electric field of effect that can be oriented parallel to along nerve, such as a vagus nerve in the patient's neck. By selecting asuitable waveform to stimulate the nerve, along with suitable parameterssuch as current, voltage, pulse width, pulses per burst, inter-burstinterval, etc., the stimulator produces a correspondingly selectivephysiological response in an individual patient. Such a suitablewaveform and parameters are simultaneously selected to avoidsubstantially stimulating nerves and tissue other than the target nerve,particularly avoiding the stimulation of nerves that produce pain.

Teachings of the present invention demonstrate how the disclosednon-invasive stimulators may be positioned and used against bodysurfaces, particularly at a location on the patient's neck under which avagus nerve is situated. Those teachings also describe the production ofcertain beneficial, therapeutic effects in a patient. However, it shouldbe understood that application of the methods and devices is not limitedto the examples that are given.

The novel systems, devices and methods for treating conditions using thedisclosed stimulator or other non-invasive stimulation devices are morecompletely described in the following detailed description of theinvention, with reference to the drawings provided herewith, and inclaims appended hereto. Other aspects, features, advantages, etc. willbecome apparent to one skilled in the art when the description of theinvention herein is taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 is a schematic view of a nerve or tissue modulating deviceaccording to the present invention, which supplies controlled pulses ofelectrical current to electrodes that are continuously in contact with avolume filled with electrically conducting material.

FIG. 2A illustrates an exemplary electrical voltage/current profile fora blocking and/or modulating impulses that are applied to a portion orportions of a nerve, in accordance with an embodiment of the presentinvention.

FIG. 2B illustrates a single burst of pulses for an electrical impulseaccording to the present invention.

FIG. 2C illustrates an ON/OFF pattern for a pair of bursts of pulsesaccording to the present invention.

FIG. 3A is a perspective view of a dual-electrode stimulator accordingto an embodiment of the present invention.

FIG. 3B is a cut-a-way view of the dual-electrode stimulator of FIG. 3A,illustrating the stimulator's electrodes and electronic components.

FIG. 4A is an exploded view of one embodiment of the head of thedual-electrode stimulator that is shown in FIG. 3A.

FIG. 4B is a cross-sectional view of the head of FIG. 4A;

FIG. 4C is an exploded view of an alternative embodiment of a head forthe dual-electrode stimulator shown in FIG. 3A.

FIG. 4D is a cross-sectional view of the head of FIG. 4C.

FIG. 5A is a perspective view of the top of an alternate embodiment of adual-electrode stimulator according to the present invention.

FIG. 5B is a perspective view of the bottom of the dual-electrodestimulator of FIG. 5A.

FIG. 5C is a cross-sectional view of the dual-electrode stimulator ofFIG. 5A.

FIG. 6 illustrates an approximate position of a housing of thedual-electrode stimulator according one embodiment of the presentinvention, when the electrodes used to stimulate the vagus nerve in theneck of a patient.

FIG. 7 illustrates the housing of the dual-electrode stimulatoraccording one embodiment of the present invention, as the electrodes arepositioned to stimulate the vagus nerve in a patient's neck viaelectrically conducting gel (or some other conducting material), whichis applied to the surface of the neck in the vicinity of the identifiedanatomical structures.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, energy is transmitted non-invasively to apatient. The invention is particularly useful for producing appliedelectrical impulses that interact with the signals of one or more nervesto achieve a therapeutic result. In particular, the present disclosuredescribes devices and methods to stimulate a vagus nerve non-invasivelyat a location on the patient's neck.

There is a long-felt but unsolved need to stimulate the vagus nerveelectrically in the neck, totally non-invasively, selectively, andessentially without producing pain. As described below, this isevidenced by the failure of others to solve the problem that is solvedby the present invention, such that investigators abandoned the attemptto non-invasively stimulate electrically in the neck, in favor ofstimulating the vagus nerve at other anatomical locations, or in favorof stimulating the vagus nerve non-electrically. Japanese patentapplication JP2009233024A with a filing date of Mar. 26, 2008, entitledVagus Nerve Stimulation System, to Fukui YOSHIHITO, is concerned withstimulation of the vagus nerve on the surface of the neck to controlheart rate, rather than epilepsy, depression, or other infirmities thatvagal nerve stimulation (VNS) is ordinarily intended to treat.Nevertheless, the approach that is taken by Yoshihito illustrates thedifficulties encountered with non-invasive electrical stimulation thevagus nerve. Yoshihito notes that because electrical stimulation on thesurface of the neck may co-stimulate the phrenic nerve that is involvedwith the control of respiration, the patient hiccups and does notbreathe normally, resulting in “a patient sense of incongruity anddispleasure.” Yoshihito's proposed solution to the problem is tomodulate the timing and intensity of the electrical stimulation at theneck as a function of the respiratory phase, in such a way that theundesirable respiratory effects are minimized. Thus, Yoshihito'sapproach is to compensate for non-selective nerve stimulation, ratherthan find a way to stimulate the vagus nerve selectively. However, suchcompensatory modulation might also prevent the stimulation fromachieving a beneficial effect in treating epilepsy, depression, andother infirmities that are ordinarily treated with VNS. Furthermore,Yoshihito does not address the problem of pain in the vicinity of thestimulation electrodes. Similar issues could conceivably arise inconnection with possible co-stimulation of the carotid sinus nerve[Ingrid J. M. Scheffers, Abraham A. Kroon, Peter W. de Leeuw. CarotidBaroreflex Activation: Past, Present, and Future. Curr Hypertens Rep12(2010):61-66]. Side effects due to co-activation of muscle that iscontrolled by the vagus nerve itself may also occur, which exemplifyanother type of non-selective stimulation [M Tosato, K Yoshida, E Toftand J J Struijk. Quasi-trapezoidal pulses to selectively block theactivation of intrinsic laryngeal muscles during vagal nervestimulation. J. Neural Eng. 4 (2007): 205-212].

One circumvention of the problem that the present invention solves is tonon-invasively stimulate the vagus nerve at an anatomical location otherthan the neck, where the nerve lies closer to the skin. A preferredalternate location is in or around the ear (tragus, meatus and/orconcha) although other locations have been proposed [Manuel L. KARELL.TENS in the Treatment of Heroin Dependency. The Western Journal ofMedicine 125 (5, 1976):397-398; Enrique C. G. VENTUREYRA. Transcutaneousvagus nerve stimulation for partial onset seizure therapy. A newconcept. Child's Nery Syst 16 (2000):101-102; T. KRAUS, K. Hosl, O.Kiess, A. Schanze, J. Kornhuber, C. Forster. BOLD fMRI deactivation oflimbic and temporal brain structures and mood enhancing effect bytranscutaneous vagus nerve stimulation. J Neural Transm 114 (2007):1485-1493; POLAK T, Markulin F, Ehlis A C, Langer J B, Ringel T M,Fallgatter A J. Far field potentials from brain stem aftertranscutaneous vagus nerve stimulation: optimization of stimulation andrecording parameters. J Neural Transm 116(10,2009):1237-1242; PatentU.S. Pat. No. 5,458,625, entitled Transcutaneous nerve stimulationdevice and method for using same, to KENDALL; U.S. Pat. No. 7,797,042,entitled Device for applying a transcutaneous stimulus or fortranscutaneous measuring of a parameter, to Dietrich et al.; patentapplication US2010/0057154, entitled Device and Method for theTransdermal Stimulation of a Nerve of the Human Body, to Dietrich et al;See also the non-invasive methods and devices that Applicant disclosedin commonly assigned co-pending U.S. patent application Ser. No.12/859,568, entitled Non-invasive Treatment of Bronchial Constriction,to SIMON]. However, it is not certain that stimulation in this minorbranch of the vagus nerve will have the same effect as stimulation of amain vagus nerve in the neck, where VNS electrodes are ordinarilyimplanted, and for which VNS therapeutic procedures producewell-documented results.

Another circumvention of the problem is to substitute electricalstimulation of the vagus nerve in the neck with some other form ofstimulation. For example, mechanical stimulation of the vagus nerve onthe neck has been proposed as an alternative to electrical stimulation[Jared M. HUSTON, Margot Gallowitsch-Puerta, Mahendar Ochani, KantaOchani, Renqi Yuan, Mauricio Rosas-Ballina, Mala Ashok, Richard S.Goldstein, Sangeeta Chavan, Valentin A. Pavlov, Christine N. Metz, HuanYang, Christopher J. Czura, Haichao Wang, Kevin J. Tracey.Transcutaneous vagus nerve stimulation reduces serum high mobility groupbox 1 levels and improves survival in murine sepsis Crit Care Med 35(12,2007):2762-2768; Artur BAUHOFER and Alexander Torossian. Mechanicalvagus nerve stimulation—A new adjunct in sepsis prophylaxis andtreatment? Crit Care Med 35 (12,2007):2868-2869; Hendrik SCHMIDT, UrsulaMuller-Werdan, Karl Werdan. Assessment of vagal activity duringtranscutaneous vagus nerve stimulation in mice. Crit Care Med 36(6,2008):1990; see also the non-invasive methods and devices thatApplicant disclosed in commonly assigned co-pending U.S. patentapplication Ser. No. 12/859,568, entitled Non-invasive Treatment ofBronchial Constriction, to SIMON]. However, such mechanical VNS has onlybeen performed in animal models, and there is no evidence that suchmechanical VNS would be functionally equivalent to electrical VNS.

Another circumvention of the problem is to use magnetic rather thanpurely electrical stimulation of the vagus nerve in the neck [Q. AZIZ etal. Magnetic Stimulation of Efferent Neural Pathways to the HumanOesophagus. Gut 33: S53-S70 (Poster Session F218) (1992); AZIZ, Q., J.C. Rothwell, J. Barlow, A. Hobson, S. Alani, J. Bancewicz, and D. G.Thompson. Esophageal myoelectric responses to magnetic stimulation ofthe human cortex and the extracranial vagus nerve. Am. J. Physiol. 267(Gastrointest. Liver Physiol. 30): G827-G835, 1994; Shaheen HAMDY, QasimAziz, John C. Rothwell, Anthony Hobson, Josephine Barlow, and David G.Thompson. Cranial nerve modulation of human cortical swallowing motorpathways. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35):G802-G808, 1997; Shaheen HAMDY, John C. Rothwell, Qasim Aziz, Krishna D.Singh, and David G. Thompson. Long-term reorganization of human motorcortex driven by short-term sensory stimulation. Nature Neuroscience 1(issue 1, May 1998):64-68; A. SHAFIK. Functional magnetic stimulation ofthe vagus nerve enhances colonic transit time in healthy volunteers.Tech Coloproctol (1999) 3:123-12; see also the non-invasive methods anddevices that Applicant disclosed in co-pending U.S. patent applicationSer. No. 12/859,568 entitled Non-invasive Treatment of BronchialConstriction, to SIMON, as well as co-pending U.S. patent applicationSer. No. 12/964,050, entitled Magnetic Stimulation Devices and Methodsof Therapy, to SIMON et al]. Magnetic stimulation might functionallyapproximate electrical stimulation. However, magnetic stimulation hasthe disadvantage that it ordinarily requires complex and expensiveequipment, and the duration of stimulation may be limited by overheatingof the magnetic stimulator. Furthermore, in some cases, magneticstimulation in the neck might also inadvertently stimulate nerves otherthan the vagus nerve, such as the phrenic nerve [SIMILOWSKI, T., B.Fleury, S. Launois, H. P. Cathala, P. Bouche, and J.P. Derenne. Cervicalmagnetic stimulation: a new painless method for bilateral phrenic nervestimulation in conscious humans. J. Appl. Physiol. 67(4): 1311-1318,1989; Gerrard F. RAFFERTY, Anne Greenough, Terezia Manczur, Michael I.Polkey, M. Lou Harris, Nigel D. Heaton, Mohamed Rela, and John Moxham.Magnetic phrenic nerve stimulation to assess diaphragm function inchildren following liver transplantation. Pediatr Crit Care Med 2001,2:122-126; W. D-C. MAN, J. Moxham, and M. I. Polkey. Magneticstimulation for the measurement of respiratory and skeletal musclefunction. Eur Respir J 2004; 24: 846-860]. Furthermore, magneticstimulation may also stimulate nerves that cause pain. Other stimulatorsthat make use of magnetic fields might also be used, but they too arecomplex and expensive and may share other disadvantages with moreconventional magnetic stimulators [Patent U.S. Pat. No. 7,699,768,entitled Device and method for non-invasive, localized neuralstimulation utilizing hall effect phenomenon, to Kishawi et al].

Transcutaneous electrical stimulation (as well as magnetic stimulation)can be unpleasant or painful, in the experience of patients that undergosuch procedures. The quality of sensation caused by stimulation dependsstrongly on current and frequency, such that currents barely greaterthan the perception threshold generally cause painless sensationsdescribed as tingle, itch, vibration, buzz, touch, pressure, or pinch,but higher currents can cause sharp or burning pain. As the depth ofpenetration of the stimulus under the skin is increased (e.g., to deepernerves such as the vagus nerve), any pain will generally begin orincrease. Strategies to reduce the pain include: use of anestheticsplaced on or injected into the skin near the stimulation and placementof foam pads on the skin at the site of stimulation [Jeffrey J.BORCKARDT, Arthur R. Smith, Kelby Hutcheson, Kevin Johnson, Ziad Nahas,Berry Anderson, M. Bret Schneider, Scott T. Reeves, and Mark S. George.Reducing Pain and Unpleasantness During Repetitive Transcranial MagneticStimulation. Journal of ECT 2006; 22:259-264], use of nerve blockades[V. HAKKINEN, H. Eskola, A. Yli-Hankala, T. Nurmikko and S. Kolehmainen.Which structures are sensitive to painful transcranial stimulation?Electromyogr. clin. Neurophysiol. 1995, 35:377-383], the use of veryshort stimulation pulses [V. SUIHKO. Modelling the response of scalpsensory receptors to transcranial electrical stimulation. Med. Biol.Eng. Comput., 2002, 40, 395-401], decreasing current density byincreasing electrode size [Kristof VERHOEVEN and J. Gert van Dijk.Decreasing pain in electrical nerve stimulation. ClinicalNeurophysiology 117 (2006) 972-978], using a high impedance electrode[N. SHA, L. P. J. Kenney, B. W. Heller, A. T. Barker, D. Howard and W.Wang. The effect of the impedance of a thin hydrogel electrode onsensation during functional electrical stimulation. Medical Engineering& Physics 30 (2008): 739-746] and providing patients with the amount ofinformation that suits their personalities [Anthony DELITTO, Michael JStrube, Arthur D Shulman, Scott D Minor. A Study of Discomfort withElectrical Stimulation. Phys. Ther. 1992; 72:410-424]. Patent U.S. Pat.No. 7,614,996, entitled Reducing discomfort caused by electricalstimulation, to RIEHL discloses the application of a secondary stimulusto counteract what would otherwise be an uncomfortable primary stimulus.

Additional considerations related to pain resulting from the stimulationare as follows. When stimulation is repeated over the course of multiplesessions, patients may adapt to the pain and exhibit progressively lessdiscomfort. Patients may be heterogeneous with respect to theirthreshold for pain caused by stimulation, including heterogeneityrelated to gender and age. Electrical properties of an individual's skinvary from day to day and may be affected by cleaning, abrasion, and theapplication of various electrode gels and pastes. Skin properties mayalso be affected by the stimulation itself, as a function of theduration of stimulation, the recovery time between stimulation sessions,the transdermal voltage, the current density, and the power density. Theapplication of multiple electrical pulses can result in differentperception or pain thresholds and levels of sensation, depending on thespacing and rate at which pulses are applied. The separation distancebetween two electrodes determines whether sensations from the electrodesare separate, overlap, or merge. The limit for tolerable sensation issometimes said to correspond to a current density of 0.5 mA/cm², but inreality the functional relationship between pain and current density isvery complicated. Maximum local current density may be more important inproducing pain than average current density, and local current densitygenerally varies under an electrode, e.g., with greater currentdensities along edges of the electrode or at “hot spots.” Furthermore,pain thresholds can have a thermal and/or electrochemical component, aswell as a current density component. Pulse frequency plays a significantrole in the perception of pain, with muscle contraction being involvedat some frequencies and not others, and with the spatial extent of thepain sensation also being a function of frequency. The sensation is alsoa function of the waveform (square-wave, sinusoidal, trapezoidal, etc.),especially if pulses are less than a millisecond in duration [Mark R.PRAUSNITZ. The effects of electric current applied to skin: A review fortransdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996):395-425].

Considering that there are so many variables that may influence thelikelihood of pain during non-invasive electrical stimulation (detailedstimulus waveform, frequency, current density, electrode type andgeometry, skin preparation, etc.), considering that these same variablescan be simultaneously selected in order to independently produce adesired therapeutic outcome by vagal nerve stimulation, and consideringthat one also wishes to selectively stimulate the vagus nerve (e.g,avoid stimulating the phrenic nerve), it is understandable that prior tothe present disclosure, no one has described devices and methods forstimulating the vagus nerve electrically in the neck, totallynon-invasively, selectively, and without causing substantial pain.

Applicant discovered the disclosed devices and methods in the course ofexperimentation with a magnetic stimulation device that was disclosed inApplicant's commonly assigned co-pending U.S. patent application Ser.No. 12/964,050, entitled Magnetic Stimulation Devices and Methods ofTherapy, to SIMON et al. Thus, combined elements in the invention do notmerely perform the function that the elements perform separately (viz.,perform therapeutic VNS, minimize stimulation pain, or stimulate thevagus nerve selectively), and one of ordinary skill in the art would nothave combined the claimed elements by known methods because thearchetypal magnetic stimulator was known only to Applicant. Thatstimulator used a magnetic coil, embedded in a safe and practicalconducting medium that was in direct contact with arbitrarily-orientedpatient skin, which had not been described in its closest art [RafaelCARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering 48 (4, 2001): 434-441; Rafael CarbunaruFAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999. (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)]. Such a design, which isadapted herein for use with surface electrodes, makes it possible toshape the electric field that is used to selectively stimulate a deepnerve such as a vagus nerve in the neck. Furthermore, the designproduces significantly less pain or discomfort (if any) to a patientthan stimulator devices that are currently known in the art. Conversely,for a given amount of pain or discomfort on the part of the patient(e.g., the threshold at which such discomfort or pain begins), thedesign achieves a greater depth of penetration of the stimulus under theskin.

FIG. 1 is a schematic diagram of a nerve stimulating/modulating device300 for delivering impulses of energy to nerves for the treatment ofmedical conditions. As shown, device 300 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and electrodes 340 coupled via wires345 to impulse generator 310.

Although a pair of electrodes 340 is shown in FIG. 1, in practice theelectrode(s) may comprises a single electrode with a large surface area,or a plurality of distinct electrode elements, each of which isconnected in series or in parallel to the impulse generator 310. Thus,the electrodes 340 that are shown in FIG. 1 represent all electrodes ofthe device collectively.

The item labeled in FIG. 1 as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asshown in the preferred embodiment, the medium is also deformable suchthat it is form-fitting when applied to the surface of the body. Thus,the sinuousness or curvature shown at the outer surface of theelectrically conducting medium 350 corresponds also to sinuousness orcurvature on the surface of the body, against which the conductingmedium 350 is applied, so as to make the medium and body surfacecontiguous. As described below in connection with a preferredembodiment, the volume 350 is electrically connected to the patient at atarget skin surface in order to shape the current density passed throughan electrode 340 that is needed to accomplish stimulation of thepatient's nerve or tissue. As also described below in connection withexemplary embodiments of the invention, the conducting medium in whichthe electrode 340 is embedded need not completely surround an electrode.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's electrodes. The signals are selected tobe suitable for amelioration of a particular medical condition, when thesignals are applied non-invasively to a target nerve or tissue via theelectrodes 340. It is noted that nerve stimulating/modulating device 300may be referred to by its function as a pulse generator. Patentapplication publications US2005/0075701 and US2005/0075702, both toSHAFER, both of which are incorporated herein by reference, relating tostimulation of neurons of the sympathetic nervous system to attenuate animmune response, contain descriptions of pulse generators that may beapplicable to the present invention. By way of example, a pulsegenerator 300 is also commercially available, such as Agilent 33522AFunction/Arbitrary Waveform Generator, Agilent Technologies, Inc., 5301Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas any externally supplied physiological signals, analog-to-digitalconverters for digitizing externally supplied analog signals,communication devices for the transmission and receipt of data to andfrom external devices such as printers and modems that comprise part ofthe system, hardware for generating the display of information onmonitors that comprise part of the system, and busses to interconnectthe above-mentioned components. Thus, the user may operate the system bytyping instructions for the control unit 330 at a device such as akeyboard and view the results on a device such as the system's computermonitor, or direct the results to a printer, modem, and/or storage disk.Control of the system may be based upon feedback measured fromexternally supplied physiological or environmental signals.Alternatively, the control unit 330 may have a compact and simplestructure, for example, wherein the user may operate the system usingonly an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes, as well as the spatial distribution ofthe electric field that is produced by the electrodes. The rise time andpeak energy are governed by the electrical characteristics of thestimulator and electrodes, as well as by the anatomy of the region ofcurrent flow within the patient. In one embodiment of the invention,pulse parameters are set in such as way as to account for the detailedanatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,Robert Szmurto, Przemystaw Ptonecki, Jacek Starzyński, StanistawWincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 2A illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe electrodes. As shown, a suitable electrical voltage/current profile400 for the blocking and/or modulating impulse 410 to the portion orportions of a nerve may be achieved using pulse generator 310. In apreferred embodiment, the pulse generator 310 may be implemented using apower source 320 and a control unit 330 having, for instance, aprocessor, a clock, a memory, etc., to produce a pulse train 420 to theelectrodes 340 that deliver the stimulating, blocking and/or modulatingimpulse 410 to the nerve. Nerve stimulating/modulating device 300 may beexternally powered and/or recharged may have its own power source 320.The parameters of the modulation signal 400, such as the frequency,amplitude, duty cycle, pulse width, pulse shape, etc., are preferablyprogrammable. An external communication device may modify the pulsegenerator programming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes,the device disclosed in patent publication No. US2005/0216062 (theentire disclosure of which is incorporated herein by reference) may beemployed. That patent publication discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type the user wishes, who can then observe the effectof this signal on a substance being treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example, the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 50 Hz, more preferably around 25Hz. The modulation signal may have a pulse width selected to influencethe therapeutic result, such as about 20 microseconds or greater, suchas about 20 microseconds to about 1000 microseconds. For example, theelectric field induced by the device within tissue in the vicinity of anerve is 10 to 600 V/m, preferably around 300 V/m. The gradient of theelectric field may be greater than 2 V/m/mm. More generally, thestimulation device produces an electric field in the vicinity of thenerve that is sufficient to cause the nerve to depolarize and reach athreshold for action potential propagation, which is approximately 8 V/mat 1000 Hz.

An objective of some embodiments of the disclosed stimulator is toprovide both nerve fiber selectivity and spatial selectivity. Spatialselectivity may be achieved in part through the design of the electrodeconfiguration, and nerve fiber selectivity may be achieved in partthrough the design of the stimulus waveform, but designs for the twotypes of selectivity are intertwined. This is because, for example, awaveform may selectively stimulate only one of two nerves whether theylie close to one another or not, obviating the need to focus thestimulating signal onto only one of the nerves [GRILL W and Mortimer JT. Stimulus waveforms for selective neural stimulation. IEEE Eng. Med.Biol. 14 (1995): 375-385].

To date, the selection of stimulation waveform parameters for vagalnerve stimulation (VNS) has been highly empirical, in which theparameters are varied about some initially successful set of parameters,in an effort to find an improved set of parameters for each patient. Amore efficient approach to selecting stimulation parameters might be toselect a stimulation waveform that mimics electrical activity in theregions of the brain that one is attempting stimulate indirectly, in aneffort to entrain the naturally occurring electrical waveform, assuggested in patent number U.S. Pat. No. 6,234,953, entitledElectrotherapy device using low frequency magnetic pulses, to THOMAS etal. and application number US20090299435, entitled Systems and methodsfor enhancing or affecting neural stimulation efficiency and/orefficacy, to GLINER et al. One may also vary stimulation parametersiteratively, in search of an optimal setting [Patent U.S. Pat. No.7,869,885, entitled Threshold optimization for tissue stimulationtherapy, to Begnaud, et al]. However, some VNS stimulation waveforms,such as those described herein, are discovered by trial and error, andthen deliberately improved upon.

Invasive vagal nerve stimulation typically uses square wave pulsesignals. In some embodiments, the typical waveform parameter values forVNS therapy for epilepsy and depression are: a current between 1 and 2mA, a frequency of between 20 and 30 Hz, a pulse width of 250-500microseconds, and a duty cycle of 10% (signal ON time of 30 s, and asignal OFF time to 5 min). Output current is gradually increased from0.25 mA to the maximum tolerable level (maximum, 3.5 mA), with typicaltherapeutic settings ranging from 1.0 to 1.5 mA. Greater output currentis associated with increased side effects, including voice alteration,cough, a feeling of throat tightening, and dyspnea. Frequency istypically 20 Hz in depression and 30 Hz in epilepsy. The therapy isadjusted in a gradual, systematic fashion to individualize therapy foreach patient. To treat migraine headaches, typical VNS parameters are acurrent of 0.25 to 1 mA, a frequency of 30 Hz, a pulse width of 500microseconds, and an ‘ON’ time of 30 s every 5 min. To treat migraineplus epilepsy, typical parameters are 1.75 mA, a frequency of 20 Hz, apulse width of 250 microseconds, and ‘ON’ time of 7 s followed by an‘OFF’ time of 12 s. To treat mild to moderate Alzheimer's disease,typical VNS waveform parameters are: a current of 0.25 to 0.5 mA, afrequency of 20 Hz, a pulse width of 500 microseconds, and an ‘ON’ timeof 30 s every 5 min. [ANDREWS, A. J., 2003. Neuromodulation.Techniques-deep brain stimulation, vagus nerve stimulation, andtranscranial magnetic stimulation. Ann. N. Y. Acad. Sci. 993, 1-13;LABINER, D. M., Ahern, G. L., 2007. Vagus nerve stimulation therapy indepression and epilepsy: therapeutic parameter settings. Acta. Neurol.Scand. 115, 23-33; G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas.Deep brain stimulation, vagal nerve stimulation and transcranialstimulation: An overview of stimulation parameters and neurotransmitterrelease. Neuroscience and Biobehavioral Reviews 33 (2009) 1042-1060].Applicant found that these square waveforms are not ideal fornon-invasive VNS stimulation as they produce excessive pain.

Prepulses and similar waveform modifications have been suggested asmeans to improve selectivity of vagus and other nerve stimulationwaveforms, but Applicant did not find them ideal [Aleksandra VUCKOVIC,Marco Tosato and Johannes J Struijk. A comparative study of threetechniques for diameter selective fiber activation in the vagal nerve:anodal block, depolarizing prepulses and slowly rising pulses. J. NeuralEng. 5 (2008): 275-286; Aleksandra VUCKOVIC, Nico J. M. Rijkhoff, andJohannes J. Struijk. Different Pulse Shapes to Obtain Small FiberSelective Activation by Anodal Blocking—A Simulation Study. IEEETransactions on Biomedical Engineering 51(5,2004):698-706; KristianHENNINGS. Selective Electrical Stimulation of Peripheral Nerve Fibers:Accommodation Based Methods. Ph.D. Thesis, Center for Sensory-MotorInteraction, Aalborg University, Aalborg, Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive VNS stimulation [M. I.JOHNSON, C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesiceffects of different pulse patterns of transcutaneous electrical nervestimulation on cold-induced pain in normal subjects. Journal ofPsychosomatic Research 35 (2/3, 1991):313-321; Patent U.S. Pat. No.7,734,340, entitled Stimulation design for neuromodulation, to DeRidder]. However, bursts of sinusoidal pulses are a preferredstimulation waveform, as shown in FIGS. 2B and 2C. As seen there,individual sinusoidal pulses have a interval of, and a burst consists ofN such pulses. This is followed by a interval with no signal (theinter-burst interval). The pattern of a burst plus followed by silentinter-burst interval repeats itself with a interval of T. For example,the sinusoidal interval may be between about 50 us to about 1 ms,preferably between about 100 us to 400 us, and more preferably about 200microseconds; the number of pulses per burst (N) maybe be between about2 to 20 pulses, preferably about 4 to 10 pulses and more preferably 5pulses; and the whole pattern of burst followed by silent inter-burstinterval may have a interval (T) of about 1 to 100 Hz, preferably about10 to 35 Hz and more preferably about 25 Hz or 40000 microseconds (amuch smaller value of T is shown in FIG. 2C to make the burstsdiscernable). Applicant is unaware of such a waveform having been usedwith vagal nerve stimulation, but a similar waveform has been used tostimulate muscle as a means of increasing muscle strength in eliteathletes. However, for the muscle strengthening application, thecurrents used (200 mA) may be very painful and two orders of magnitudelarger than what is disclosed herein for VNS. Furthermore, the signalused for muscle strengthening may be other than sinusoidal (e.g.,triangular), and the parameters, N, and T may also be dissimilar fromthe values exemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J.Rose, and R. C. Lehman. Electrical stimulation of the quadriceps femorisin an elite weight lifter: a single subject experiment. Int J Sports Med10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation: The Early Experiments. Physical Therapy 82 (10,2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88(10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89(2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2,2009): 170-181]. Byway of example, the electric field shown in FIGS. 2B and 2C may have anEmax value of 17 V/m, which is sufficient to stimulate the vagus nervebut is significantly lower than the threshold needed to stimulatesurrounding muscle.

In order to compare the stimulator that is disclosed herein withexisting electrodes and stimulators used for non-invasive electricalstimulation, it is useful to first summarize the relevant physics ofelectric fields and currents that are produced by the electrodes.According to Maxwell's equation (Ampere's law with Maxwell correction):∇×B=J+∈ (∂E/∂t), where B is the magnetic field, J is the electricalcurrent density, E is the electric field, E is the permittivity, and tis time [Richard P. FEYNMAN, Robert B. Leighton, and Matthew Sands. TheFeynman Lectures on Physics. Volume II. Addison-Wesley Publ. Co.(Reading Mass., 1964), page 15-15].

According to Faraday's law, ∇× E=−∂B/∂t. However, for present purposes,changes in the magnetic field B may be ignored, so ∇× E=0, and E maytherefore be obtained from the gradient of a scalar potential ϕ: E=−∇ϕ.In general, the scalar potential ϕ and the electric field E arefunctions of position (r) and time (t).

The electrical current density J is also a function of position (r) andtime (t), and it is determined by the electric field and conductivity asfollows, where the conductivity σ is generally a tensor and a functionof position (r): J=σE=−σ∇ϕ

Because ∇∇×B=0, Ampere's law with Maxwell's correction may be writtenas: ∇·1+∇·∈ (∂E/∂t)=0. If the current flows in material that isessentially unpolarizable (i.e., is presumed not to be a dielectric sothat ∈=0), substitution of the expression for J into the aboveexpression for Ampere's law gives −V·(σ∇ϕ which is a form of Laplace'sequation. If the conductivity of material in the device (or patient) isitself a function of the electric field or potential, then the equationbecomes non-linear, which could exhibit multiple solutions, frequencymultiplication, and other such non-linear behavior. The equation hasbeen solved analytically for special electrode configurations, but formore general electrode configurations, it can be solved numerically[Petrus J. CILLIERS. Analysis of the current density distribution due tosurface electrode stimulation of the human body. Ph.D. Dissertation,Ohio State University, 1988. (UMI Microform Number: 8820270, UMICompany, Ann Arbor Mich.); Martin REICHEL, Teresa Breyer, Winfried Mayr,and Frank Rattay. Simulation of the Three-Dimensional Electrical Fieldin the Course of Functional Electrical Stimulation. Artificial Organs26(3,2002):252-255; Cameron C. McINTYRE and Warren M. Grill. FiniteElement Analysis of the Current-Density and Electric Field Generated byMetal Microelectrodes. Annals of Biomedical Engineering 29 (2001):227-235; A. PATRICIU, T. P. DeMonte, M. L. G. Joy, J. J. Struijk.Investigation of current densities produced by surface electrodes usingfinite element modeling and current density imaging. Proceedings of the23rd Annual EMBS International Conference, Oct. 25-28, 2001, Istanbul,Turkey: 2403-2406; Yong H U, X B Xie, L Y Pang, X H Li K D K Luk.Current Density Distribution Under Surface Electrode on Posterior TibialNerve Electrical Stimulation. Proceedings of the 2005 IEEE Engineeringin Medicine and Biology 27th Annual Conference Shanghai, China, Sep.1-4, 2005: 3650-3652]. The equation has also been solved numerically inorder to compare different electrode shapes and numbers [Abhishek DATTA,Maged Elwassif, Fortunato Battaglia and Marom Bikson. Transcranialcurrent stimulation focality using disc and ring electrodeconfigurations: FEM analysis. J. Neural Eng. 5 (2008) 163-174; Jay T.RUBENSTEIN, Francis A. Spelman, Mani Soma and Michael F. Suesserman.Current Density Profiles of Surface Mounted and Recessed Electrodes forNeural Prostheses. IEEE Transactions on Biomedical Engineering BME-34(11,1987): 864-875; David A. KSIENSKI. A Minimum Profile Uniform CurrentDensity Electrode. IEEE Transactions on Biomedical Engineering 39(7,1992): 682-692; Andreas KUHN, Thierry Keller, Silvestro Micera,Manfred Morari. Array electrode design for transcutaneous electricalstimulation: A simulation study. Medical Engineering & Physics 31 (2009)945-951]. The calculated electrical fields may be confirmed usingmeasurements using a phantom [A. M. SAGI_DOLEV, D. Prutchi and R. H.Nathan. Three-dimensional current density distribution under surfacestimulation electrodes. Med. and Biol. Eng. and Comput. 33(1995):403-408].

If capacitive effects cannot be ignored, an additional term involvingthe time-derivative of the gradient of the potential appears in the moregeneral expression, as obtained by substituting the expressions for Jand E into the divergence of Ampere's law with Maxwell's correction:−∇·(σ∇ϕ∇·(∈∇ϕ(∂ϕ∂t))

The permittivity E is a function of position (r) and is generally atensor. It may result from properties of the body and may also be aproperty of the electrode design [L. A. GEDDES, M. Hinds and K. S.Foster. Stimulation with capacitor electrodes. Med. and Biol. Eng. andComput. 25(1987):359-360]. As a consequence of such a term, the waveformof the electrical potential at points within the body will generally bealtered relative to the waveform of the voltage signal(s) applied to theelectrode(s). Furthermore, if the permittivity of a material in thedevice itself (or patient) is a function of the electric field orpotential, then the equation becomes non-linear, which could exhibitmultiple solutions, frequency multiplication, and other such non-linearbehavior. This time-dependent equation has been solved numerically [KUHNA, Keller T. A 3D transient model for transcutaneous functionalelectrical stimulation. Proc. 10th Annual Conference of theInternational FES Society July 2005—Montreal, Canada: pp. 1-3; AndreasKUHN, Thierry Keller, Marc Lawrence, Manfred Morari. A model fortranscutaneous current stimulation: simulations and experiments. MedBiol Eng Comput 47(2009):279-289; N. FILIPOVIC, M. Nedeljkovic, A.Peulic. Finite Element Modeling of a Transient Functional ElectricalStimulation. Journal of the Serbian Society for Computational Mechanics1 (1, 2007):154-163; Todd A. KUIKEN, Nikolay S. Stoykov, Milica Popovic,Madeleine Lowery and Allen Taflove. Finite Element Modeling ofElectromagnetic Signal Propagation in a Phantom Arm. IEEE Transactionson Neural Systems and Rehabilitation Engineering 9 (4,2001): 346-354].

In any case, Dirichlet (D) boundary conditions define voltage sources,and Neumann (N) boundary conditions describe the behavior of theelectric field at the crossover boundary from skin to air, as follows:N:∂ϕ∂nσ(r) and D:ϕV(t)where n denotes the outward pointing normal vector, i.e., the vectororthogonal to the boundary curve; and V(t) denotes the voltage appliedto an electrode. Thus, no conduction current can flow across anair/conductor interface, so according to the interfacial boundaryconditions, the component of any current normal to the an air/conductorinterface should be zero. In constructing the above differentialequation for ϕ as a function of time, the divergence of J is taken,which satisfies the continuity equation: ∇·J=−∂ ∂t, where is the chargedensity. Conservation of charge requires that sides of this equationequal zero everywhere except at the surface of the electrode wherecharge is impressed upon the system (injected or received).

It is an objective of some embodiments of the present invention to shapean elongated electric field of effect that can be oriented parallel to along nerve such as the vagus nerve in the neck. The term “shape anelectric field” as used herein means to create an electric field or itsgradient that is generally not radially symmetric at a given depth ofstimulation in the patient, especially a field that is characterized asbeing elongated or finger-like, and especially also a field in which themagnitude of the field in some direction may exhibit more than onespatial maximum (i.e. may be bimodal or multimodal) such that the tissuebetween the maxima may contain an area across which current flow isrestricted. Shaping of the electric field refers both to thecircumscribing of regions within which there is a significant electricfield and to configuring the directions of the electric field withinthose regions. Our invention does so by configuring elements that arepresent within the equations that were summarized above, comprising (butnot limited to) the following exemplary configurations that may be usedalone or in combination.

First, different contours or shapes of the electrodes affect ∇·J. Forexample, charge is impressed upon the system (injected or received)differently if an electrode is curved versus flat, or if there are morethan two electrodes in the system.

Second, values of the voltage V(t) in the above boundary condition ismanipulated to shape the electric field. For example, if the devicecontains two pairs of electrodes that are perpendicular or at a variableangle with respect to one another, the waveform of the voltage acrossone pair of electrodes may be different than the waveform of the voltageacross the second pair, so that the superimposed electric fields thatthey produce may exhibit beat frequencies, as has been attempted withelectrode-based stimulators [Patent U.S. Pat. No. 5,512,057, entitledInterferential stimulator for applying localized stimulation, to REISSet al.], and acoustic stimulators [Patent No. U.S. Pat. No. 5,903,516,entitled Acoustic force generator for detection, imaging and informationtransmission using the beat signal of multiple intersecting sonic beams,to GREENLEAF et al].

Third, the scalar potential ϕ in the above equation ∂ϕ ∂n σ(r) may bemanipulated to shape the electric field. For example, this isaccomplished by changing the boundaries of conductor/air (ornon-conductor) interfaces, thereby creating different boundaryconditions. For example, the conducting material may pass throughconducting apertures in an insulated mesh before contacting thepatient's skin, creating thereby an array of electric field maxima. Asanother example, an electrode may be disposed at the end of a long tubethat is filled with conducting material, or the electrode may besituated at the bottom of a curved cup that is filled with conductingmaterial. In those cases the dimensions of the tube or cup would affectthe resulting electric fields and currents.

Fourth, the conductivity (in the equation J=σE) may be varied spatiallywithin the device by using two or more different conducting materialsthat are in contact with one another, for given boundary conditions. Theconductivity may also be varied by constructing some conducting materialfrom a semiconductor, which allows for adjustment of the conductivity inspace and in time by exposure of the semiconductor to agents to whichthey are sensitive, such as electric fields, light at particularwavelengths, temperature, or some other environmental variable overwhich the user of the device has control. For the special case in whichthe semiconductor's conductivity may be made to approach zero, thatwould approximate the imposition of an interfacial boundary condition asdescribed in the previous paragraph.

Fifth, a dielectric material having a high permittivity E, such asMylar, neoprene, titanium dioxide, or strontium titanate, may be used inthe device, for example, in order to permit capacitative electricalcoupling to the patient's skin. Changing the permittivity in conjunctionalong with changing the waveform V(t) would especially affect operationof the device, because the permittivity appears in a term that is afunction of the time-derivative of the electric potential: ∇·(∈∇(∂ϕ∂t))

In configurations of the present invention, an electrode is situated ina container that is filled with conducting material. In one embodiment,the container contains holes so that the conducting material (e.g., aconducting gel) can make physical contact with the patient's skinthrough the holes. For example, the conducting medium 350 in FIG. 1 maycomprise a chamber surrounding the electrode, filled with a conductivegel that has the approximate viscosity and mechanical consistency of geldeodorant (e.g., Right Guard Clear Gel from Dial Corporation, 15501 N.Dial Boulevard, Scottsdale Ariz. 85260, one composition of whichcomprises aluminum chlorohydrate, sorbitol, propylene glycol,polydimethylsiloxanes Silicon oil, cyclomethicone, ethanol/SD Alcohol40, dimethicone copolyol, aluminum zirconium tetrachlorohydrex gly, andwater). The gel, which is less viscous than conventional electrode gel,is maintained in the chamber with a mesh of openings at the end wherethe device is to contact the patient's skin. The gel does not leak out,and it can be dispensed with a simple screw driven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient. Rather thanusing agar as the conducting medium, an electrode can instead be incontact with in a conducting solution such as 1-10% NaCl that alsocontacts an electrically conducting interface to the human tissue. Suchan interface is useful as it allows current to flow from the electrodeinto the tissue and supports the conducting medium, wherein the devicecan be completely sealed. Thus, the interface is material, interposedbetween the conducting medium and patient's skin, that allows theconducting medium (e.g., saline solution) to slowly leak through it,allowing current to flow to the skin. Several interfaces are disclosedas follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.Another example is the KM10T hydrogel from Katecho Inc., 4020 GannettAve., Des Moines Iowa 50321.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the electrode and conducting solutionin from the tissue, yet allow current to pass.

The stimulator 340 in FIG. 1 shows two equivalent electrodes,side-by-side, wherein electrical current would pass through the twoelectrodes in opposite directions. Thus, the current will flow from oneelectrode, through the tissue and back through the other electrode,completing the circuit within the electrodes' conducting media that areseparated from one another. An advantage of using two equivalentelectrodes in this configuration is that this design will increase themagnitude of the electric field gradient between them, which isimportant for exciting long, straight axons such as the vagus nerve inthe neck and other deep peripheral nerves.

A preferred embodiment of the stimulator is shown in FIG. 3A. Across-sectional view of the stimulator along its long axis is shown inFIG. 3B. As shown, the stimulator (30) comprises two heads (31) and abody (32) that joins them. Each head (31) contains a stimulatingelectrode. The body of the stimulator (32) contains the electroniccomponents and battery (not shown) that are used to generate the signalsthat drive the electrodes, which are located behind the insulating board(33) that is shown in FIG. 3B. However, in other embodiments of theinvention, the electronic components that generate the signals that areapplied to the electrodes may be separate, but connected to theelectrode head (31) using wires. Furthermore, other embodiments of theinvention may contain a single such head or more than two heads.

Heads of the stimulator (31) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (34) that also serves as an on/off switch. A light(35) is illuminated when power is being supplied to the stimulator. Acap (36) is provided to cover each of the stimulator heads (31), toprotect the device when not in use, to avoid accidental stimulation, andto prevent material within the head from leaking or drying. Thus, inthis embodiment of the invention, mechanical and electronic componentsof the stimulator (impulse generator, control unit, and power source)are compact, portable, and simple to operate. A cap (36) is provided tocover each of the stimulator heads (31), to protect the device when notin use, to avoid accidental stimulation, and to prevent material withinthe head from leaking or drying. However, for embodiments of thestimulator head in which the head is covered with Mykir or some otherhigh-dielectric material that can capacitively couple the signal to theskin, the Mylar may completely seal the gel within the stimulator head,thereby preventing exposure of the gel to the outside. In that case,there would be no gel evaporation. Then, the cap (36) would be lessadvantageous because the head can be cleaned between stimulationsessions (e.g., with isopropyl alcohol) with no chance of contaminatingthe internal gel.

Construction of the stimulator head is shown in more detail in FIG. 4.In the embodiment shown in FIGS. 4A and 4B, the stimulator head containsan aperture screen, but in the embodiment shown in FIGS. 4C and 4D,there is no aperture screen. Referring now to the exploded view shown inFIG. 4A, the electrode head is assembled from a snap-on cap (41) thatserves as a tambour for a conducting membrane (42), an aperture screen(43), the head-cup (44), the electrode which is also a screw (45), and alead-mounting screw (46) that is inserted into the electrode (45). Theelectrode (45) seen in each stimulator head has the shape of a screwthat is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the above-mentionedequations for the electrical potential may have a solution correspondingmore closely to a far-field approximation. Rounding of the electrodesurface or making the surface with another shape will likewise affectthe boundary conditions. Completed assembly of the stimulator head isshown in FIG. 4B, which also shows how the head is attached to the bodyof the stimulator (47).

As examples, the conducting membrane (42) may be a sheet of Tecophlicmaterial from Lubrizol Corporation, 29400 Lakeland Boulevard, Wickliffe,Ohio 44092. The apertures may be open, or they may be plugged withconducting material, for example, KM10T hydrogel from Katecho Inc., 4020Gannett Ave., Des Moines Iowa 50321. If the apertures are so-plugged,the conducting membrane (42) becomes optional. The head-cup (44) isfilled with conducting material, for example, SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.The snap-on cap (41), aperture screen (43), head-cup (44) and body ofthe stimulator are made of a non-conducting material, such asacrylonitrile butadiene styrene. The depth of the head-cup from its topsurface to the electrode may be between one and six centimeters. Thehead-cup may have a different curvature than what is shown in FIG. 4, orit may be tubular or conical or have some other inner surface geometrythat will affect the Neumann boundary conditions.

The stimulator is preferably configured such that the distribution ofcurrent passing into the patient's tissue is substantially uniform tominimize high current densities that would potentially cause pain to thepatient. In one exemplary embodiment, the electrode(s) are preferablyspaced from the conducting membrane 42 by a distance of about 0.25 to 4times the diameter of the conducting membrane 42. Thus, if the diameterof the conducting membrane 42 is 1 inch then the electrode should bebetween 0.25 and 4 inches from the conducting membrane, preferably about0.5 to 2 inches. In addition, in order to reach a nerve at a depth d,the electrode diameter should be between 0.2 and 2 d, preferable about 1d and the spacing (from center to center) should be between 1.5 d and 3d, preferable about 2 d. The conducting medium preferably has aconductivity that is high enough to allow current flow therethrough, butlow enough to minimize a non-uniform distribution of current passingthrough the conducting membrane 42 into the patient's tissue.

The alternate embodiment of the stimulator head that is shown in FIG. 4Calso contains a snap-on cap (41), a conducting membrane (42), thehead-cup (44), the electrode which is also a screw (45), and alead-mounting screw (46) that is inserted into the electrode (45). Thisalternate embodiment differs from the embodiment shown in FIGS. 4A and4B in regard to the mechanical support that is provided to theconducting membrane (42). Whereas the aperture screen had providedmechanical support to the membrane in the other embodiment, in thealternate embodiment a reinforcing ring (40) is provided to themembrane. That reinforcement ring rests on non-conducting struts (49)that are placed in the head-cup (44), and a non-conducting strut-ring(48) is placed within notches in the struts (49) to hold the struts inplace. An advantage of the alternate embodiment is that withoutapertures, current flow is less restricted through the conductingmembrane (42). Furthermore, although the struts and strut-ring are madeof non-conducting material in this alternate embodiment, the design maybe adapted to position additional electrode or other conducting elementswithin the head-cup for other more specialized configurations of thestimulator head, the inclusion of which will influence the electricfields that are generated by the device. Completed assembly of thealternate stimulator head is shown in FIG. 4D, without showingattachment to the body of the stimulator, and without showing theinsertion of the lead-mounting screw (46). In fact, it is also possibleto insert a lead under the head of the electrode (45), and many othermethods of attaching the electrode to the signal-generating electronicsof the stimulator are known in the art.

Another embodiment of the stimulator is shown in FIG. 5, showing adevice in which electrically conducting material is dispensed from thedevice to the patient's skin. FIGS. 5A and 5B respectively provide topand bottom views of the outer surface of the electrical stimulator 50.FIG. 5C provides a bottom view of the stimulator 50, after sectioningalong its long axis to reveal the inside of the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 1), and the power-levelcontroller is attached to the control unit (330 in FIG. 1) of thedevice. The power source battery and power-level controller, as well asthe impulse generator (310 in FIG. 1) are located (but not shown) in therear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 inFIG. 1) to the stimulator's electrodes 56. The two electrodes 56 areshown here to be elliptical metal discs situated between the headcompartment 57 and rear compartment 55 of the stimulator 50. A partition58 separates each of the two head compartments 57 from one another andfrom the single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 1) to each headcompartment 57. Each partition 58 may also slide towards the head of thedevice in order to dispense conducting gel through the mesh apertures51. The position of each partition 58 therefore determines the distance59 between its electrode 56 and mesh openings 51, which is variable inorder to obtain the optimally uniform current density through the meshopenings 51. The outside housing of the stimulator 50, as well as eachhead compartment 57 housing and its partition 58, are made ofelectrically insulating material, such as acrylonitrile butadienestyrene, so that the two head compartments are electrically insulatedfrom one another.

In the preferred embodiments, electrodes are made of a metal, such asstainless steel. However, in other embodiments, the electrodes may havemany other sizes and shapes, and they may be made of other materials[Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade, 18(2,2008):35-45; G. M. LYONS, G. E. Leane, M.Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigation of theeffect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1,1994):29-35].

For example, there may be more than two electrodes; the electrodes maycomprise multiple concentric rings; and the electrodes may bedisc-shaped or have a non-planar geometry. They may be made of othermetals or resistive materials such as silicon-rubber impregnated withcarbon that have different conductive properties [Stuart F. COGAN.Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng.2008. 10:275-309; Michael F. NOLAN. Conductive differences in electrodesused with transcutaneous electrical nerve stimulation devices. PhysicalTherapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 3 to 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6,2005):448-452; Dejan B. POPOVIC andMirjana B. Popovic. Automatic determination of the optimal shape of asurface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 3to 5 provide a uniform surface current density, which would otherwise bea potential advantage of electrode arrays, and which is a trait that isnot shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jørgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12,2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6,2006): 368-381;Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman. Imaging ofNonuniform Current Density at Microelectrodes by ElectrogeneratedChemiluminescence. Anal. Chem. 71(1999): 4944-4950]. In fact, patientsfound the design shown in FIGS. 3 to 5 to be less painful in a directcomparison with a commercially available grid-pattern electrode[UltraStim grid-pattern electrode, Axelggard Manufacturing Company, 520Industrial Way, Fallbrook Calif., 2011].

The stimulator designs shown in FIGS. 3 to 5 situate the electroderemotely from the surface of the skin within a chamber, with conductingmaterial placed in the chamber between the skin and electrode. Such achamber design had been used prior to the availability of flexible,flat, disposable electrodes [Patent U.S. Pat. No. 3,659,614, entitledAdjustable headband carrying electrodes for electrically stimulating thefacial and mandibular nerves, to Jankelson; U.S. Pat. No. 3,590,810,entitled Biomedical body electode, to Kopecky; U.S. Pat. No. 3,279,468,entitled Electrotherapeutic facial mask apparatus, to Le Vine; U.S. Pat.No. 6,757,556, entitled Electrode sensor, to Gopinathan et al; U.S. Pat.No. 4,383,529, entitled Iontophoretic electrode device, method and gelinsert, to Webster; U.S. Pat. No. 4,220,159, entitled Electrode, toFrancis et al. U.S. Pat. Nos. 3,862,633, 4,182,346, and 3,973,557,entitled Electrode, to Allison et al; U.S. Pat. No. 4,215,696, entitledBiomedical electrode with pressurized skin contact, to Bremer et al; andU.S. Pat. No. 4,166,457, entitled Fluid self-sealing bioelectrode, toJacobsen et al.] The stimulator designs shown in FIGS. 3 to 5 are alsoself-contained units, housing the electrodes, signal electronics, andpower supply. Portable stimulators are also known in the art, forexample, U.S. Pat. No. 7,171,266, entitled Electro-acupuncture devicewith stimulation electrode assembly, to Gruzdowich]. One of thenovelties or the present invention is that two or more remote electrodesare configured for placement relative to the axis of a deep, long nerve,such that the stimulator along with a correspondingly suitablestimulation waveform shapes the electric field, producing a selectivephysiological response by stimulating that nerve, but avoidingsubstantial stimulation of nerves and tissue other than the targetnerve, particularly avoiding the stimulation of nerves that producepain.

Examples in the remaining disclosure will be directed to methods forusing the disclosed electrical stimulation devices for treating apatient. These applications involve stimulating the patient in andaround the patient's neck. However, it will be appreciated that thesystems and methods of the present invention might be applied equallywell to other nerves of the body, including but not limited toparasympathetic nerves, sympathetic nerves, and spinal or cranialnerves. As examples, the disclosed devices may used to treat particularmedical conditions, by substituting the devices disclosed herein for thestimulators disclosed in the following patent applications.

Applicant's commonly assigned co-pending patent application, Ser. No.12/964,050, entitled Magnetic Stimulation Devices and Methods ofTherapy, disclosed methods for using the device to treat such conditionsas post-operative ileus, dysfunction associated with TNF-alpha inAlzheimer's disease, postoperative cognitive dysfunction, rheumatoidarthritis, bronchoconstriction, urinary incontinence and/or overactivebladder, and sphincter of Oddi dysfunction.

Another commonly assigned co-pending application Ser. No. 13/005,005,entitled Non-invasive Treatment of Neurodegenerative Diseases, disclosedmethods and devices for treating neurodegenerative diseases moregenerally, including essential tremor, Alzheimer's disease and itsprecursor mild cognitive impairment (MCI), Parkinson's disease(including Parkinson's disease dementia) and multiple sclerosis, as wellas postoperative cognitive dysfunction and postoperative delirium. Thedevices and methods may also be used to treat conditions that were notdisclosed in those patent applications, such as allergic rhinitis,headaches, particularly tension headaches, cluster headaches, sinusheadaches and migraine headaches [Alberto Proietti CECCHINI, Eliana Mea,Vincenzo Tullo, Marcella Curone, Angelo Franzini, Giovanni Broggi, MarioSavino, Gennaro Bussone, Massimo Leone. Vagus nerve stimulation indrug-resistant daily chronic migraine with depression: preliminary data.Neurol Sci (2009) 30 (Suppl 1):S101-S104].

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3 to 5 to stimulatethe vagus nerve at that location in the neck, in which the stimulatordevice 50 in FIG. 5 is shown to be applied to the target location on thepatient's neck as described above. For reference, locations of thefollowing vertebrae are also shown: first cervical vertebra 71, thefifth cervical vertebra 75, the sixth cervical vertebra 76, and theseventh cervical vertebra 77.

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin. The vagusnerve 60 is identified in FIG. 7, along with the carotid sheath 61 thatis identified there in bold peripheral outline. The carotid sheathencloses not only the vagus nerve, but also the internal jugular vein 62and the common carotid artery 63. Features that may be identified nearthe surface of the neck include the external jugular vein 64 and thesternocleidomastoid muscle 65. Additional organs in the vicinity of thevagus nerve include the trachea 66, thyroid gland 67, esophagus 68,scalenus anterior muscle 69, and scalenus medius muscle 70. The sixthcervical vertebra 76 is also shown in FIG. 7, with bony structureindicated by hatching marks.

If it is desired to maintain a constant intensity of stimulation in thevicinity of the vagus nerve (or any other nerve or tissue that is beingstimulated), methods may also be employed to modulate the power of thestimulator in order to compensate for patient motion or other mechanismsthat would otherwise give rise to variability in the intensity ofstimulation. In the case of stimulation of the vagus nerve, suchvariability may be attributable to the patient's breathing, which mayinvolve contraction and associated change in geometry of thesternocleidomastoid muscle that is situated close to the vagus nerve(identified as 65 in FIG. 7). Methods for compensating for motion andother confounding factors were disclosed by the present applicant incommonly assigned co-pending application Ser. No. 12/859,568, entitledNon-Invasive Treatment of Bronchial Constriction, to SIMON, which ishereby incorporated by reference.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. The position and angular orientation of thedevice are adjusted about that location until the patient perceivesstimulation when current is passed through the stimulator electrodes.The applied current is increased gradually, first to a level wherein thepatient feels sensation from the stimulation. The power is thenincreased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 6 or 7).The stimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient. Stimulationparameters for each patient are adjusted on an individualized basis.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a time-varying sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect. For example, thehypothalamus is well known to be responsive to the presence of brightlight, so exposing the patient to bright light that is fluctuating withthe same stimulation frequency as the vagus nerve (or a multiple of thatfrequency) may be performed in an attempt to enhance the role of thehypothalamus in producing the desired therapeutic effect. Such pairedstimulation does not rely upon neuronal plasticity and is in that sensedifferent from other reports of paired stimulation [Navzer D. ENGINEER,Jonathan R. Riley, Jonathan D. Seale, Will A. Vrana, Jai A. Shetake,Sindhu P. Sudanagunta, Michael S. Borland and Michael P. Kilgard.Reversing pathological neural activity using targeted plasticity. Nature(2011): published online doi:10.1038/nature09656].

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. A method comprising: generating anelectrical signal within a housing having a lead extending therefrom;varying the electric field with a signal generator within the housingsuch that burst periods and constant periods are created, wherein theelectric field has a charge that alternates between positive andnegative during the burst periods, wherein the charge of the electricfield alternates between positive and negative 2 times to 20 timesduring each burst period, and wherein the charge of the electric fieldis constant during each constant period; positioning the lead near, orin operational proximity to, a spinal nerve within a patient; andemitting the electrical signal via the lead towards the spinal nervesuch that an electric field is generated near the spinal nerve such thatthe patient experiences at least some pain relief.
 2. The method ofclaim 1, wherein the lead includes an electrode, and further comprisingpositioning the electrode near, or in operational proximity to, thespinal nerve and applying a voltage to the electrode such that theelectric field is generated.
 3. The method of claim 2, furthercomprising varying the voltage such that the electric field includes theburst periods and the constant periods.
 4. The method of claim 1,wherein the charge of the electric field alternates between positive andnegative 4 and 10 times during each burst period.
 5. The method of claim1, wherein the burst periods have a frequency of about 1 to about 100Hz.
 6. The method of claim 1, wherein each burst period has a durationof less than about 20,000 microseconds.
 7. A device comprising: ahousing; a lead extending from the housing, wherein the lead isconfigured to be positioned near, or in operational proximity to, aspinal nerve; and a source of energy positioned within the housing,wherein the source of energy is operably coupled to the lead; a signalgenerator configured for generating an electrical field such that theelectrical field is emitted via the lead towards the spinal nerve suchthat that a patient experiences at least some pain relief, wherein thesignal generator is configured to vary the electrical field to createburst periods and constant periods, wherein the electric field has acharge that alternates between positive and negative during the burstperiods, wherein the charge of the electric field alternates betweenpositive and negative 2 and 20 times during each burst period andwherein the charge of the electric field is constant during eachconstant period.
 8. The device of claim 7 further comprising one or moreelectrodes coupled to the source of energy, wherein the source of energyapplies a voltage to the electrode(s) to generate the electric field. 9.The device of claim 7, wherein the burst periods have a frequency ofabout 1 to about 100 Hz.
 10. The device of claim 7, wherein the electricfield emitted during the constant periods has a magnitude of about zero.11. The device of claim 7, wherein each burst period has a duration ofless than about 20,000 microseconds.